The brain's ability to adapt to experience during development and in adulthood has long been considered the biological basis for learning and memory. Neuronal plasticity at the level of synapses has been recognized and studied for decades. More recently, reports of activity- and learning-dependent changes in myelination have brought forth the concept of myelin as an additional form of brain plasticity that can mediate long-lasting changes in neural circuit function. In parallel, myelin deficits have been implicated in the etiology and symptomology of numerous neurodevelopmental and neurodegenerative diseases. In some rodent models of neurodevelopmental disorders, behavioral deficits can be significantly attenuated by treatment with a pro- myelinating drug, indicating that defects in myelination could be central to the manifestation of certain nervous system diseases. Despite these hints at the importance of myelination in neuronal circuit maturation and function, due to a lack of gain and loss-of-function tools, it has been difficult to evaluate how myelination actually impacts the underlying neural circuits. A recent study from our lab identified a relationship between the extent of myelination and the density of excitatory synapses in the developing rodent cortex, raising the possibility that myelin can shape neural circuits by modulating synapse formation and/or elimination. However, many related questions remain unanswered. Does myelination only impact specific populations of synapses? Does the change in synapse density result from a change in synapse generation or synapse elimination? Can myelination modulate functional neuronal plasticity, in addition to structural plasticity? To better define how myelination affects synapse dynamics and cortical plasticity, this proposal will use recently developed genetic mouse models to evaluate the effects of manipulating the extent of myelination on synaptogenesis and synapse loss. The adolescent visual cortex will be used as a model for plasticity, as it displays well-described functional and structural plasticity in response to visual deprivation. The central hypothesis is that myelination promotes synapse stability and restricts experience-dependent neuronal plasticity in the developing cortex. Aim I will test whether enhancing or impairing myelination changes the density of both excitatory and inhibitory synapses in the developing cortex. Aim II will test whether manipulating myelination affects synapse generation and/or elimination during normal visual cortex development and following visual deprivation. Aim III will test whether enhancing or impairing myelination can restrict or prolong the critical period for functional neuronal plasticity in the visual cortex following visual deprivation. The results from these studies will further our understanding of how myelin shapes neuronal plasticity and have broad implications for diseases in which synapses or myelination are perturbed.